PROJECT ABSTRACT This proposal details a five-year plan to prepare the candidate, Kathleen M. Buchheit, MD, for a career as an independent translational investigator positioned to impact our understanding of allergic and immunologic disease. The proposed investigations focus on the role of interleukin (IL)-5 and local immunoglobulins driving respiratory tract inflammation and mast cell activation in aspirin-exacerbated respiratory disease (AERD). AERD is characterized by asthma, severe chronic rhinosinusitis with nasal polyposis, excessive cysteinyl leukotriene and prostaglandin production, and respiratory reactions to cyclooxygenase-1 inhibitors. The candidate has observed that patients with AERD have a unique population of plasma cells that express high levels of IL-5 receptor at both the transcript and protein levels. Additionally, she has discovered that subjects with AERD have aberrant local nasal polyp immunoglobulin production, which correlates with nasal polyp severity, and also demonstrate elevated nasal polyp IgE and IgG4 as compared to aspirin-tolerant patients. Employing cellular and molecular techniques, the candidate will test the hypotheses that a unique subset of IL- 5 receptor-driven nasal polyp plasma cells drives production of pathogenic immunoglobulins in the respiratory tract in AERD, and that the pathogenic immunoglobulin production can be mitigated by targeting IL-5 with mepolizumab. These studies will advance our understanding of the pathogenesis of AERD leading to the identification of novel therapeutic targets for this disease. During the period of support the candidate will leverage her clinical experience in the treatment of nasal polyposis and AERD, the regional and national referral patient base at her institution?s AERD center, and her laboratory skills while she further develops skills in mechanistically-focused clinical study design, computational biostatistics for high- dimensional data analysis, team leadership, and scientific writing. Dr. Buchheit will work under the mentorship of Tanya Laidlaw, MD and Joshua Boyce, MD, experts in AERD and mechanisms of inflammation. Additionally, Dr. Buchheit has assembled a team of extraordinary physician-scientists including Drs. Shiv Pillai, Frances Eun-Hyung Lee, Soumya Raychaudhuri, and Peter Weller, who have committed their time, resources, and expertise to facilitate her career development and research goals. Their mentorship and the scientific and clinical environment at BWH, along with the translational work and career development plan, will position the candidate to secure independent NIH funding and to establish herself as a physician-scientist with a focus on mechanistic clinical trials in AERD and chronic rhinosinusitis.